The objective of this proposal is to study the deterioration in brain function that takes place before neuronal loss occurs in tauopathy, a group of neurodegenerative disorders involving the tau protein that includes Alzheimer's disease, by specifically addressing the following basic question: What is the molecular basis of memory loss in tauopathy? We showed that neurofibrillary tangles, a cardinal neuropathological feature of Alzheimer's disease, contributed very little to cognitive dysfunction (SantaCruz et al., Science, 2005). This work led us to believe that an as yet unknown post-translationally modified form of the tau protein is instead responsible, and we propose in the current application to identify this entity, which we call tau* (tau star). We discovered a post-translationally modified form of the amyloid-[unreadable] (A[unreadable]) protein in the brain, called A[unreadable]*56 (A beta star 56), that causes memory loss when injected into normal animals (Lesn[unreadable] et al., Nature, 2006). The discovery of A[unreadable]*56 is the first time that the principles used to identify etiological agents of infectious diseases have been applied to determine the etiology of cognitive dysfunction in a non-infectious neurodegenerative disorder. Whether this approach can be extended to tau and tauopathy is the challenge we will undertake if we are given a EUREKA award. This work will not only pave a new way to think about how to approach the problem of neurodegenerative diseases, but will also lead the research effort to understand the molecular species involved in the pathogenesis of Alzheimer's disease. Understanding this pathogenesis is clearly central if we are to develop rational and mechanistic therapies for this disorder, which currently affects 5 million Americans and may reach 16 million by the year 2050. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to determine the molecular basis of memory loss in tauopathy. We propose that memory loss is caused by an as yet unknown posttranslationally modified form the tau protein, which we call tau* (tau star). To find tau* we shall adapt the principles that have allowed for the identification of etiological agents of infectious diseases, which include the identification of candidate tau species that correlate with memory loss, the isolation of these species, and their application to neuronal and murine experimental systems to assay their biological activity.